Consanguinity in northwest Pakistan: evidence of temporal decline.

Pakistan has a high burden of hereditary and congenital anomalies and their incidence rate almost doubles against the background of parental consanguinity. Consanguineous unions (CU) are customary in Pakistan and deeply rooted socio-cultural norms favour CU. This study aimed to elucidate the determinants and temporal change in CU in four northwestern populations of Pakistan. In a cross-sectional study, data on marital union types, bio-demographic factors, and paternal consanguinity were collected from 6,323 ever-married individuals in four districts of northwest Pakistan: Haripur, Muzaffarabad, Mansehra, and Shangla. We used descriptive statistics and multivariable logistic regression analysis. The CU were calculated to be 55%, and inbreeding coefficient F (ICF) was estimated to be 0.029. Eight factors, including district, rural origin, age of husband, occupational group of husband, literacy of husband, parental consanguinity, exchange marriage, and extended family type, were found to be significant predictors of consanguinity in the multivariable logistic regression analysis. The rate of consanguinity decreased significantly in the younger age categories of individuals. The rate of CU was seen to be declining over time and in marriages that started 'before 1980' and 'after 2010', respectively, and there was a decline in ICF from 0.030 to 0.027. These analyses also showed that the literacy rate improved, the average age at marriage increased, and the frequency of exchange marriages decreased over time. This study employs a sizable first-hand dataset to demonstrate a lowering CU rate in northwest Pakistan. It is anticipated that the burden of inherited and congenital anomalies may likely to diminish in the study populations along with the fall in ICF.

A Stop-gain Variant c.220C>T (p.(Gln74*)) in FLNB Segregates with Spondylocarpotarsal Synostosis Syndrome in a Consanguineous Family.

Spondylocarpotarsal synostosis (SCT) syndrome is a very rare and severe form of skeletal dysplasia. The hallmark features of SCT are disproportionate short stature, scoliosis, fusion of carpal and tarsal bones, and clubfoot. Other common manifestations are cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia. Homozygous variants in FLNB are known to cause SCT. This study was aimed to investigate the phenotypic and genetic basis of unique presentation of SCT syndrome segregating in a consanguineous Pakistani family. Three of the four affected siblings evaluated had severe short stature, short trunk, short neck, kyphoscoliosis, pectus carinatum, and winged scapula. The subjects had difficulty in walking and gait problems and complained of knee pain and backache. Roentgenographic examination of the eldest patient revealed gross anomalies in the axial skeleton including thoracolumbar and cervical fusion of ribs, severe kyphoscoliosis, thoracic and lumbar lordosis, coxa valga, fusion of certain carpals and tarsals, and clinodactyly. The patients had normal faces and lacked other typical features of SCT like cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia. Whole exome sequencing (WES) of two affected siblings led to the discovery of a rare stop-gain variant c.220C>T (p.(Gln74*)) in exon 1 of the FLNB gene. The variant was homozygous and segregated with the malformation in this family. This study reports extensive phenotypic variability in SCT and expands the mutation spectrum of FLNB.

Prevalence pattern, phenotypic manifestation, and descriptive genetics of congenital limb deficiencies in Pakistan.

BACKGROUND: Congenital limb deficiency (CLD) is a group of very rare disorders characterized by substantial hypoplasia or the complete absence of 1 or more bones of limbs. Congenital limb deficiency has a significant physical, clinical, and psychological burden on the affected individuals and their families. This cross-sectional study aimed to describe the prevalence pattern, phenotypic manifestations, and biodemographic factors associated with CLD in a cohort assembled from the Pakistani population from the Northwestern region. METHODS: Through a prospective cross-sectional study, 141 individuals having 166 limbs with CLD were recruited during 2017-2021. RESULTS: There were 77 (55%) individuals with transverse defects, 61 (43%) with longitudinal defects, and 3 (2%) with Intercalary defects. Among the patients with transverse defects, 52 had terminal amputations and 25 had symbrachydactyly. Among the longitudinal defects, thumb aplasia/hypoplasia was the most common presentation (20 patients), followed by oligodactyly (18), and radial hemimelia (18). Eighty six percent had upper-limb deficiencies, 83% had unilateral deficiencies, and 92% were sporadic in nature. The parental consanguinity was observed in 33% individuals, and 79% cases had an isolated presentation which may be indicative of the substantial role of nongenetic factors in the etiology of CLD. CONCLUSIONS: This study demonstrates marked heterogeneity in CLD subtypes in the involvement of limbs and associated variables. There is a need to establish a national registry for CLD, molecular genetic diagnosis, and multidisciplinary medical and social rehabilitation services for these individuals.

Burden of Congenital and Hereditary Anomalies in Hazara Population of Khyber Pakhtunkhwa, Pakistan.

Background and Objectives: In Pakistan, there is high incidence of congenital and hereditary anomalies (CA) which are a leading cause of infant mortality and morbidity. In order to elucidate the burden and biodemographic correlates of CA, this study was aimed to report the prevalence-pattern and phenotypic attributes of CA in the Hazara population of Khyber Pakhtunkhwa, Pakistan. Methods: In a retrospective cross-sectional study, subjects/families with CA were recruited from district hospitals and community centers. Phenotypic and descriptive data were obtained; pedigrees were analyzed and parental and biodemographic attributes were recorded. Results: A total of 1,189 independent subjects and/or families with CA were ascertained. The malformations were grouped into nine major and 95 minor categories. Neurological disorder had the highest representation (n=486; proportion=0.409; 95% CI=0.381-0.437), followed by limb defects (n=292; proportion=0.246, 95% CI=0.221-0.270), musculoskeletal defects, sensorineural/ear defects, blood disorders, eye/visual impairments, ectodermal anomalies, and congenital heart defects. In this cohort, sporadic cases were 65% and familial 35%. Parental consanguinity was significantly higher in isolated cases compared to syndromic, and in familial cases compared to sporadic. Further, speech apraxia and epilepsy were most common associations among the syndromic cases. The assessment of variables like demography, parental consanguinity, familial/sporadic nature, and pedigree structures showed conspicuous heterogeneity among the major and minor categories of CA. Conclusions: The trend of CA and high incidence of sporadic cases observed in this cohort indicate that nongenetic factors may play a significant role in their etiology which could be minimized by improving the healthcare system.

The first adolescent case of Fraser syndrome 3, with a novel nonsense variant in GRIP1.

Fraser syndrome is characterized by cryptophthalmos, syndactyly and other autopod defects, and abnormalities of the respiratory and urogenital tracts. Biallelic variants in GRIP1 can cause Fraser syndrome 3 (FRASRS3), and five unrelated FRASRS3 cases have been reported to date. Four cases are fetuses with homozygous truncating variants. The remaining case is an almost 9-year-old Turkish girl compound heterozygous for a truncation variant and a possibly frame-shift intragenic deletion. We present a 15.5-year old Pakistani boy with homozygous truncating variant c.1774C>T (p.Gln592Ter). Of the hallmarks of the disease, the boy has cryptophthalmia, midface retrusion, very low anterior hairline, hair growth on temples extending to the supraorbital line and also on alae nasi, agenesis of right kidney, and cutaneous syndactyly of fingers and toes but no symptoms in any other organs, including lungs, anorectal system, genitalia, and umbilical system. This case is the oldest known individual with FRASRS3, and our findings show that a homozygous GRIP1 truncating variant can manifest with a non-lethal phenotype than in the reported cases with such variants, expanding the phenotypic and mutational spectrum of GRIP1.